Malaria parasite developed themselves as resistant to a variety of anti-malarial drugs which matters as a strong challenge to medicinal chemists to develop and search for new anti-malarial drugs.
The compound artemisinin, also known as Qinghaosu (QHS), isolated in 1971 from the Chinese medicinal plant Artemisia annua is inexpensive and used as traditional chinese medicine against malaria.
Artemisinin and its simple derivatives artemether, arteether and sodium artesunate have gained importance over the years as a new generation of antimalarial drugs, especially in the treatment of multi-drug-resistant malaria strains. However these ‘first generation’ derivatives suffer from poor oral bioavailability and short plasmatic half-life.
Replacement of the oxygen at the C-10 position with carbon could be expected to produce compounds i.e. so-called ‘second generation’ compounds not only with greater hydrolytic stability but also with a longer half life and potentially lower toxicity. Consequently several groups have developed synthetic and semi-synthetic approaches to C-10 carba-analogues of artemisinin (J. Med. Chem. 1999, 42, 5487; ibid 2000, 43, 4228; Tetrahedron, 1999, 55, 3625; Bioorg. Med. Chem. Lett 2005, 15, 2629; U.S. Pat. No. 5,142,328, Mexican patent 236235, 2006).
In addition to this antimalarial activity, it has been shown that some artemisinin derivatives and dimers have anti-cancer properties (J. Med. Chem. 2003, 46, 987-994; U.S. Pat. No. 6,790,863; U.S. Pat. No. 5,677,468).
Over the past twenty years only a few drugs isolated from higher plants have yielded clinical agents, the outstanding examples being vinblastine and vincristine from the Madagascan periwinkle, Catharanthus roseus, etoposide, the semi-synthetic lignam, from May-apple Podophyllum peltatum and the diterpenoid taxol, commonly referred to as paclitaxel, from the Pacific yew, Taxus brevifolia. Of these agents, paclitaxel is the most exciting, recently receiving approval from the United States Food and Drug Administration for the treatment of refractory ovarian cancer. Since the isolation of artemisinin, there has been a concerted effort by investigators to study other therapeutic applications of artemisinin and its derivatives.
National Institutes of Health reported that artemisinin is inactive against P388 leukemia (See NCI Report on NSC 369397 tested on 25 Oct. 1983). Later anticancer studies that have been conducted on cell line panels consisting of 60 lines organized into nine, disease-related subpanels including leukemia, non-small-cell lung cancer, colon, CNS, melanoma, ovarian renal, prostate and breast cancers, further confirm that artemisinin displays very little anticancer activity. A series of artemisinin-related endoperoxides were tested for cytoxicity to Ehrlich ascites tumor (EAT) cells using the microculture tetrazolum (MTT) assay (H. J. Woerdenbag, et al. “Cytotoxicity of Artemisinin-Related Endoperoxides to Ehrlich Ascites Tumor Cells,” Journal of Natural Products 1993, 56 (6), 849-856). The MTT assay, used to test the artemisinin-related endoperoxides for cytoxicity, is based on the metabolic reduction of soluble tetrazolium salts into insoluble colored formazan products by mitochondrial dehydrogenase activity of the tumor cells. As parameters for cytoxicity, the IC50 and IC80 values, the drug concentrations causing respectively 50% and 80% growth inhibition of the tumor cells, were used. Artemisinin, had an IC50 value of 29.8 μM. Derivatives of dihydroartemisinin (DHA) being developed as antimalarial drugs (artemether, arteether, sodium artesunate, artelinic acid and sodium artelinate), exhibited a somewhat more potent cytoxicity. Their IC50 values ranged from 12.2 μM to 19.9 μM. The DHA condensation by-product, disclosed previously by M. Cao, et al., 1984, was the most potent cytotoxic agent, its IC50 being 1.4 μM. At this drug concentration the condensation by-product, is approximately twenty-two times more cytoxic than artemisinin and sixty times more cytotoxic than DHA. There is still a need, therefore, for developing structural analogs of artemisinin as antitumor agents that have potency equivalent or greater than known anticancer agents.